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Genet Med. 2019 Nov;21(11):2532-2542. doi: 10.1038/s41436-019-0523-0. Epub 2019 Apr 30.

Recessive variants in ZNF142 cause a complex neurodevelopmental disorder with intellectual disability, speech impairment, seizures, and dystonia.

Author information

1
Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA.
2
Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
3
Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad, Pakistan.
4
Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
5
Institut für Humangenetik, Technische Universität München, Munich, Germany.
6
Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Parkville, Australia.
7
Department of Neurology, P.J. Safarik University, Kosice, Slovak Republic.
8
Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic.
9
Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan.
10
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia.
11
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, and University of Melbourne Department of Medical Biology and School of Mathematics and Statistics, Parkville, VIC, Australia.
12
University of Melbourne Department of Paediatrics, Royal Children's Hospital, and Florey and Murdoch Children's Research Institute, Parkville, VIC, Australia.
13
Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany.
14
Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General Faculty Hospital, Prague, Czech Republic.
15
Institute of Medical Genetics, Medical School of Vienna, Vienna, Austria.
16
Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA. nicholas.katsanis@duke.edu.
17
Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany. juliane.winkelmann@tum.de.
18
Institut für Humangenetik, Technische Universität München, Munich, Germany. juliane.winkelmann@tum.de.
19
Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany. juliane.winkelmann@tum.de.
20
Munich Cluster for Systems Neurology, SyNergy, Munich, Germany. juliane.winkelmann@tum.de.

Abstract

PURPOSE:

The purpose of this study was to expand the genetic architecture of neurodevelopmental disorders, and to characterize the clinical features of a novel cohort of affected individuals with variants in ZNF142, a C2H2 domain-containing transcription factor.

METHODS:

Four independent research centers used exome sequencing to elucidate the genetic basis of neurodevelopmental phenotypes in four unrelated families. Following bioinformatic filtering, query of control data sets, and secondary variant confirmation, we aggregated findings using an online data sharing platform. We performed in-depth clinical phenotyping in all affected individuals.

RESULTS:

We identified seven affected females in four pedigrees with likely pathogenic variants in ZNF142 that segregate with recessive disease. Affected cases in three families harbor either nonsense or frameshifting likely pathogenic variants predicted to undergo nonsense mediated decay. One additional trio bears ultrarare missense variants in conserved regions of ZNF142 that are predicted to be damaging to protein function. We performed clinical comparisons across our cohort and noted consistent presence of intellectual disability and speech impairment, with variable manifestation of seizures, tremor, and dystonia.

CONCLUSION:

Our aggregate data support a role for ZNF142 in nervous system development and add to the emergent list of zinc finger proteins that contribute to neurocognitive disorders.

KEYWORDS:

ataxia; childhood apraxia of speech; developmental delay; dolichocephaly; homozygosity mapping

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